Norepinephrine is a very high yield topic. We give it a 5 out of 5. It's a must-know
for exams and boards. It's also known as Noradrenaline in some places in the world, or the common
brand name is Levophed. It is a natural hormone and a neurotransmitter. Natural hormone means
that it's produced naturally in our bodies, it doesn't need to be synthesized in a lab.
It's a catecholamine, just like epinephrine and dopamine and, in fact, it's synthesized
from dopamine in the sympathetic nervous system and also in the chromaffin cells of the adrenal
medulla. Lastly, it's a nonselective Alpha and Beta 1 agonist, meaning that it agonizes
Alpha 1, Alpha 2 and Beta 1. If you compare this to Epinephrine, Norepinephrine does not
stimulate the Beta 2 receptor very well at all. Now, on to the mechanism of action of
Norepinephrine. Norepinephrine is an agonist of the Alpha 1, Alpha 2 and Beta 1 adrenoceptors,
and if you were to break that down further, it would be more of a stimulant for the Alphas
than for Beta 1. So, physiologically, what does that mean? Well, that makes Norepinephrine
a great presser drug. Let's talk about why and break down the effects of all three of
these: Alpha 1, Alpha 2 and Beta 1. So, the Alpha 1 stimulation causes the peripheral
vasculature to constrict down very tightly, increasing the peripheral vascular resistance,
thus increasing the systolic and diastolic blood pressure. So, now on to the Beta 1 receptor.
Well, so usually we see with a Beta 1 stimulation, an increase in the chronotropy, ionotropy
and dromotropy of the heart. However, in Norepinephrine's case, what we see physiologically is more
an increase in the ionotropy, or the contractility, and the reason for that is that there is such
an increase in the pressures that you actually get a compensatory baroreceptor-mediated reflex
bradycardia that over-powers the Beta 1 action of tachycardia. So, the heart is beating harder,
but just not necessarily faster. And, as for the Alpha 2, well, I don't have bullet points
for it, because it is lower-yield than three. Remember back, Alpha 2 is a feedback inhibitor,
it inhibits, or slows the release of Norepinephrine that is naturally released from sympathetic
nerves. But, we're not talking about nerves that are being stimulated naturally right
now. We're talking about nerves that are being stimulated by a drug that you gave the patient.
These effects are happening because there's a lot of Norepinephrine floating around in
the system that we gave the patient, not because there's a lot of Norepinephrine being released
from the presynaptic nerve. So, what is the difference between Norepinephrine and Epinephrine
on the body? Well, because Norepinephrine isn't great about stimulating Beta 2s, the
effect is sometimes called "unopposed Alpha 1." So, remember, Alpha 1s are constrictors,
Beta 2s are dilators. So, because there's no, or at least very little, Beta 2 stimulation,
you get strong, unopposed clamping of the vasculature. And this does a really great
job of increasing the pressures. So, let's look over at our graph here and talk about
what's going on. First off, heart rate. We've already kind of talked about this. Norepinephrine
is a Beta 1 agonist, or a Beta 1 stimulator. Normally, that would increase the speed and
the strength at which the heart beats. However, in this case, Norepinephrine does such a good
job at increasing the pressure, that baroreceptors, through an increase in vagal tone, actually
cause a reflex bradycardia. As for the blood pressure, we break this down into two parts
again, remember, systolic and diastolic. Systolic is going to go way up, the resistance that
it's beating against is greatly increased, so it's going to be quite a bit higher. The
diastolic pressure is also going to go up. This is because there is very little Beta
2 stimulation to balance the strong Alpha 1. And lastly, of course, as I've said several
times, the peripheral vascular resistance is going to up a lot. So, what are the clinical
uses of Norepinephrine? Well, because it's such a good presser, we use it mostly in cases
of severe hypotension or septic shock, and both of these should make sense because Norepinephrine
increases both the systolic and diastolic blood pressure. Two really important side
effects for Norepinephrine include: Cardiac arrhythmias, which makes sense because we're
stimulating the heart, and if it's prone to any kind of arrhythmia, this could just push
it over the edge. Also, it increases the risk of myocardial infarction and this is because
we're increasing the workload, which increases the oxygen demand and, in a heart that perhaps
has narrowed vessels or stenosis, this could just be the straw that broke the camel's back.
Okay, how about a Knowledge Challenge! Based on what you know of the mechanism of action,
which is Alpha 1 and 2 and Beta 1 stimulation, what is another possible side effect of norepinephrine?
How about Bradycardia. Alright, so why? Remember, we're stimulating the Beta 1 receptor, right?
And that usually increases chronotropy, right? Yes, but remember: We are really increasing
the blood pressure here, we're making the heart pump harder and we're pumping that blood
through a smaller hole because we're clamping down the peripheres. That shoots the blood
pressure way up. Our body naturally responds to this increase in blood pressure through
a feedback loop that is beyond the scope of this lecture. There is an increase in vagal
tone to the heart and the heart beats slower, so, believe it or not, bradycardia is another
possible side effect of norepinephrine. So, if you picked A, good job, let's move on.
Oh, wait a minute, why is Urinary retention a possible side effect? This is one of the
problems with Norepinephrine. It clamps down on things, not just vessels, but smooth muscle
in general, and this includes the smooth muscle in the urine outflow track. Think of this:
What about the drug Tamsulosin? Tamsulosin is often given to patients with benign prostatic
hyperplasia. Tamsulosin is an Alpha 1 antagonist - so on the flip side of that coin, Norepinephrine
is an Alpha 1 agonist, therefore, it is going to be harder to pee when you're taking Norepinephrine.
So, if you picked A and B, good job. Let's move on. Wait a minute! What about Tremor?
We're really stimulating the adrenergic system. Remember, this is the fight or flight response,
so you could be tremulous. And, I think you know where I'm going with this, D is also
another possible side effect. We're clamping down on things and that includes small vessels
in the toes and the fingers. So, if you picked all four, good job.